The abuse of heroin is a serious, growing problem worldwide. Injection drug use (IDU) associated with heroin abuse is strongly correlated with the spread of hepatitis and HIV and the latter to the spread of drug-resistant tuberculosis. In Brazil, Argentina, China, and six other countries, IDU was shown to have seeded the HIV epidemic in the heterosexual population. U.S. heroin availability has continued to increase in the last decade as producers in Mexico rapidly increase production of low cost, high-purity white heroin (vs. the much less pure traditional black-tar heroin) in order to gain more of the market share. This is reflected in Mexican opium poppy cultivation that more than tripled between 2013-2016 reaching an estimated potential pure heroin production of 81 metric tons for 2016. The abuse of fentanyl and designer analogs is escalating rapidly and in 2016 these drugs were responsible for about 20,000 overdose fatalities exceeding those where heroin was the causative agent. Although the increasing availability of nasal Narcan, (antidote for acute narcotic overdose) has saved many lives, the tightening of controls on prescription narcotics has driven many dependent users to the much cheaper (per dose) heroin and heroin-fentanyl mixtures. These disturbing trends are exacerbated by the fact that there is no completely successful treatment and prevention for opiate addiction. Although the presently available therapies (buprenorphine or methadone replacement and depot naltrexone) are effective, new treatment options are needed to combat the growing abuse of heroin, fentanyl and other designer opioids and the continuing problem of HIV transmission. The extent of the opioid abuse problem is keenly appreciated when it is recognized that the estimated combined total U.S. cost of the opioid epidemic in 2017 was $115 billion and that the cost by 2020 is estimated to be an additional $500 billion more. One of these strategies we are currently pursuing for treatment and prevention of opiate abuse is the is the ultimate development of a combination trivalent (or separate) anti-heroin anti-HIV antifentanyl vaccine(s). A successful combination vaccine of this type would suppress heroin and fentanyl abuse and protect against HIV infection from any route of exposure. Injection drug use is a major factor in the transmission of HIV-1. Suppression of the accompanying needle sharing would limit the spread of HIV and hepatitis in injection drug users. Such a vaccine should also be a valuable adjunct to prevent relapse in newly abstinent former narcotic abusers. This is an important consideration as the relapse rate for those able to quit is as high as 60% in the first year. We are continuing to prepare and evaluate experimental vaccines based on our novel approach of utilization of metabolically stable heroin-mimetic haptens. These haptens were then covalently attached to the highly immunogenic tetanus toxoid (TT) with or without and HIV component and formulated with the Army Liposome Formulation. One such vaccine was derived from our lead heroin hapten 6-Amhap. The TT-6-AmHap vaccine significantly reduced heroin-induced antinociception and locomotion behavioral changes. We also examined the efficacy of the TT-6-AmHap vaccine in mice in the locomotion assay after a high-dose heroin challenge. We administered heroin at 50 mg/kg SC and found partial protection even at this dose of 50 times the ED50. This level of protection may be sufficient to suppress fatal overdose in humans. Competition ELISA demonstrated that 6-AmHap-induced antibodies bound heroin and its metabolites, 6-acetylmorphine, morphine, and other abused opioids, including oxycodone, hydrocodone and hydromorphone. The antibodies did not cross-react with the therapies for substance abuse or the overdose rescue drug naloxone. The HIV portion of one of our vaccines related to TT-6-AmHap utilized a cyclic V2 (cV2) peptide previously identified as a correlate of prevention of acquisition of HIV in the RV144 phase III clinical trial. RV144 is the only HIV vaccine trial that has demonstrated efficacy to date. We immunized mice and sera were assessed for antibody titer to heroin and cV2. We assessed efficacy against heroin by subcutaneous heroin challenge. Antibody titers to cV2 were in the millions and bound to gp120 and gp70V1V2. The heroin-HIV vaccine induced protection against heroin challenge and afforded a very high titer cV2 antibodies, a proposed a correlate of efficacy in RV144. We conclude that an effective heroin-HIV vaccine is feasible based on our data.